title: Metoclopramide stimulates catecholamine- and granin-derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 (5-HT4) receptors.
abstract: The gastroprokinetic agent metoclopramide is known to stimulate catecholamine secretion from pheochromocytomas. The aim of the study was to investigate the mechanism of action of metoclopramide and expression of serotonin type 4 (5-HT(4)) receptors in pheochromocytoma tissues. Tissue explants, obtained from 18 pheochromocytomas including the tumor removed from a 46-year-old female patient who experienced life-threatening hypertension crisis after metoclopramide administration and 17 additional pheochromocytomas (9 benign and 8 malignant) were studied. Cultured pheochromocytoma cells derived from the patient who previously received metoclopramide were incubated with metoclopramide and various 5-HT(4) receptor ligands. In addition, total mRNAs were extracted from all the 18 tumors. Catecholamine- and granin-derived peptide concentrations were measured in pheochromocytoma cell incubation medium by HPLC and radioimmunological assays. In addition, expression of 5-HT(4) receptor mRNAs in the 18 pheochromocytomas was investigated by the use of reverse transcriptase-PCR.
  
  
  RESULTS
  Metoclopramide and the 5-HT(4) receptor agonist cisapride were found to activate catecholamine- and granin-derived peptide secretions by cultured tumor cells. Metoclopramide- and cisapride-evoked catecholamine- and granin-derived peptide productions were inhibited by the 5-HT(4) receptor antagonist GR 113808. 5-HT(4) receptor mRNAs were detected in the patient's tumor and the series of 17 additional pheochromocytomas. This study shows that pheochromocytomas express functional 5-HT(4) receptors that are responsible for the stimulatory action of metoclopramide on catecholamine- and granin-derived peptide secretion. All 5-HT(4) receptor agonists must therefore be contraindicated in patients with proven or suspected pheochromocytoma.
authors.affiliation: INSERM U413, University of Rouen, Mont Saint Aignan, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Guillemot
authors.forename: Patricia
authors.initials: P
authors.lastname: Compagnon
authors.forename: Dorthe
authors.initials: D
authors.lastname: Cartier
authors.forename: Erwan
authors.initials: E
authors.lastname: Thouennon
authors.forename: Christian
authors.initials: C
authors.lastname: Bastard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lihrmann
authors.forename: Perrine
authors.initials: P
authors.lastname: Pichon
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Plouin
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Youssef
authors.initials: Y
authors.lastname: Anouar
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Kuhn
authors.forename: Laurent
authors.initials: L
authors.lastname: Yon
authors.forename: Hervé
authors.initials: H
authors.lastname: Lefebvre
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000313:Adrenal Medulla / Q000166:cytology / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D002864:Chromogranins / Q000378:metabolism; D020117:Cisapride / Q000494:pharmacology; D000075202:Contraindications; D004294:Domperidone / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008787:Metoclopramide / Q000494:pharmacology*; D008875:Middle Aged; D010673:Pheochromocytoma / Q000188:drug therapy* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D002395:Catecholamines; D002864:Chromogranins; D018492:Dopamine Antagonists; D012333:RNA, Messenger; D017366:Serotonin Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; D004294:Domperidone; D008787:Metoclopramide; D020117:Cisapride